This project is dedicated to discovering ways to induce regeneration of the corticospinal tract (CST) and recovery of motor function after spinal cord injury (SCI). The CST is the pathway that is responsible for the ability to move voluntarily. Damage to the CST as a result of a spinal cord injury is the reason people are paralyzed. The present project is based on recent extraordinary discoveries that the CST can be induced to regenerate following spinal cord injury by targeting molecular pathways that control cell growth in development, specifically phosphatase and tensin inhibitor (PTEN). PTEN is responsible for shutting down the type of protein synthesis that is critical for cell growth during development. PTEN acts by blocking the mammalian target of rapamycin, (mTOR), so deletion of PTEN releases inhibition on mTOR, which in turn allows the cell to synthesize proteins that are critical for cell growth. Importantly, the same molecular pathways are also the key to allowing neurons to regenerate their axons following injury. Based on this, recent studies have shown that genetic deletion of PTEN in mice allows neurons to mount a robust regenerative response. Most critically, our studies demonstrate that when PTEN is deleted in neurons in the cerebral cortex, the neurons that give rise to the CST are able to robustly regenerate their axons after SCI. The fact that regeneration of the CST can be successfully induced provides us with an unprecedented opportunity to address a question that is central to regeneration research-whether it is possible to induce regeneration in a therapeutically-relevant time frame and whether inducing CST regeneration is enough to restore circuits of sufficient specificity to allow some degree of restoration of motor function. The project uses anatomical and physiological methods to assess the degree to which regenerated axons grow along normal tracts, to normal targets, form functional synapses, and contribute to motor function. Pre-clinical experiments will also assess whether it is possible to down-regulate PTEN in a therapeutically-relevant time frame and using non-genetic interventions. PUBLIC HEALTH RELEVANCE: This project builds upon the novel discovery that axon regeneration can be induced following spinal cord injury by targeting molecular pathways that control cell growth during development. The project will assess whether it is possible to target these molecular pathways in a therapeutically relevant time frame and whether the regeneration is sufficient to restore motor function.